Abstract: Gastroparesis (GP) presents with chronic upper GI dysmotility symptoms in the setting of delayed gastric emptying without any mechanical obstruction. Inconsistencies exist between subjective symptom severity and objective evidence of GP, and available therapies are limited by accompanying adverse events and unpredictable efficacy. Hence the pathophysiology, clinical course, outcomes and treatment strategies require further investigation. Our response to the NIDDK Gastroparesis Consortium (U01) under RFA-DK-16-010 has the following aims: 1) To complete approved studies initiated by the GpCRC which entails enrolling GP patients to Gastroparesis Registry 2 with their clinical data and bio-samples as well as obtain gastric tissue under the pathological basis of gastroparesis (PBG) protocol, when some patients undergo surgery for failed medical therapy. This data collection will contribute more knowledge about pathogenesis, pathomorphology, symptoms severity grading, complications, treatment outcomes in patients with GP and gastroparesis-like presentation but normal gastric emptying. 2) As a new diagnostic strategy, we propose to determine whether endoscopic ultrasound (EUS)- guided core biopsy samples of antral muscularis propria in GP patients can provide sufficient tissue for full histologic analysis to specifically address status of interstitial cell of Cajal, myenteric plexus neurons and smooth muscle pathology. After reconfirming the safety and success of this methodology in a study of 30 patients receiving both endoscopic and surgical biopsies all patients entering GpR3 as well as GpR2 registry will undergo EUS guided core biopsies of the antral muscularis propria as part of the database. Therefore we will investigate whether this endoscopic method can safely replace surgery to obtain smooth muscle tissue and correlate ICC findings with symptoms, gastric emptying and treatment outcome. 3) We propose to investigate the therapeutic efficacy of a new Dopamine D2/D3 antagonist in gastroparetic patients of either diabetic or idiopathic etiology by performing a multicenter, double- blind, randomized, placebo-controlled, parallel three-group study which will also assess cardiac safety and adverse event. The plan is for the NIH to partner with one of the 2 pharmaceutical companies developing new agents, Dopamine D2/D3 antagonists with no cardiac toxicity. All GpR3 patients will be invited to enroll into 2 parallel 12 week trials for diabetic and idiopathic etiologies of gastroparesis. If we are awarded this grant, TTU research team is committed to facilitate the execution of the protocols and collaborate with other Centers under GpCRC and NIDDK/NIH supervision.